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Biomedical Roger Narayan Editor

Biomedical Materials

123 Editor Roger Narayan Department of University of North Carolina, Chapel Hill 152 MacNider Hall Chapel Hill, NC 27599-1175 USA roger [email protected]

ISBN 978-0-387-84871-6 e-ISBN 978-0-387-84872-3 DOI 10.1007/978-0-387-84872-3

Library of Congress Control Number: 2008939136

c Springer Science+Business Media, LLC 2009 All rights reserved. This work may not be translated or copied in whole or in part without the written permission of the publisher (Springer Science+Business Media, LLC, 233 Spring Street, New York, NY 10013, USA), except for brief excerpts in connection with reviews or scholarly analysis. Use in connection with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed is forbidden. The use in this publication of trade names, trademarks, service marks, and similar terms, even if they are not identified as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights.

Printed on acid-free paper springer.com A Historical Perspective on the Development of Biomedical Materials

There have been enormous strides in the development of novel biomedical materials over the past three decades. A biomedical (also known as a biomaterial) is a , metal, ceramic, or natural material that provides structure and/or function to an implantable . In one generation, a large number of biodegradable , bioactive ceramics, and wear-resistant metal alloys have made their way from research laboratories into widely-used medical devices. This heavy flurry of recent progress by materials scientists has partially overshadowed the efforts of surgeons, who previously led research efforts to develop biomedical materials. Until the 1960’s, surgeons were at the forefront of efforts to find new materials for use in medical prostheses. Surgeons were driven by their clinical duties to improve the treatment of those suffering from congenital malformations, trauma, or disease. These surgeon-scientists attempted to alleviate patient suffering using “off-the-shelf” materials, which were developed for nonmedical applications. This brief historical perspective describes some initial efforts to develop novel biomedi- cal materials. Bronze or copper have been used for thousands of years to repair fractured . However, use of bronze or copper was limited due to copper accumulation in the eyes, liver, brain, and other body tissues. Two developments in the late nineteenth century accelerated the use of synthetic materials in the . The develop- ment of the X-ray revealed that conventional external treatments were insufficient and stimulated the development of internal fixation procedures. In addition, broad acceptance of Lister’s antiseptic procedures allowed for internal treatment of medi- cal conditions with minimal risk of infection. Lister himself used antiseptic proce- dure to successfully suture fractured patellae with silver wire in 1885. Themistocles Gluck described replacement of both the acetabulum (pelvis) and femur ( ) using carved ivory at the 10th International Medical Congress in 1890; however, bone resorption and concomitant infection eventually caused these prostheses to fail. Neither acceptable materials nor designs were available at the time to fabricate medical devices. Surgeons made several advances in biomedical materials development in the early- to mid- twentieth century. At the turn of the century, many European surgeons were experimenting with celluloid, rubber, magnesium, zinc, and other materials. In 1924, A. A. Zierold described an animal study on the interaction between bone

v vi A Historical Perspective on the Development of Biomedical Materials and several metals, including aluminum, aluminum alloy, copper, low carbon steel, cobalt-chromium alloy, gold, iron, lead, magnesium, nickel, silver, and zinc. X-ray and histological sections of canine bone-material interface revealed that gold, silver, stellite, lead, and aluminum were encapsulated by tissue and were well-tolerated by the animals. Venable, Stuck, and Beach demonstrated the electrolysis of implanted biomedical materials in a 1937 study. They placed aluminum, brass, carbon, cobalt- chromium alloy, copper, galvanized iron, gold, lead, magnesium, nickel, silver, stainless steel, vanadium steel, and zinc in bones of experimental animals. Their bio- chemical, radiographic and clinical findings demonstrated that ion transfer between different metals in the body occurred in accordance with electromotive force. Their work also demonstrated that cobalt-chromium alloy was essentially nonelectrolytic; this material has remained a mainstay medical alloy to the present day. The orthopedic surgeon Sir John Charnley, made several significant advances in the field of biomedical materials, including (a) the introduction of the metal-ultra high molecular weight bearing couple; (b) the use of poly (methyl methacrylate) for fixation; (c) the reduction of postoperative sepsis due to the use of laminar flow air-handling systems and prophylactic antibiotics; and (d) the place- ment of antibiotics in . In the 1950’s, Charnley discovered that natural joints exhibit boundary lubrication. He then attempted to find a synthetic material with similarly low frictional properties. His first choice for an acetabular cup ma- terial, polytetrafluoroethylene, demonstrated poor wear properties. Unfortunately, this issue only became evident after a large clinical trial involving polytetrafluo- roethylene implants had begun. More than three hundred polytetrafluoroethylene had to be revised due to poor wear properties, necrosis, and im- plant loosening. Charnley’s laboratory assistant subsequently examined ultra high molecular weight polyethylene, which had found use in mechanical looms. Charn- ley noted that: (a) polyethylene had better wear characteristics than polytetrafluo- roethylene; and (b) polyethylene was capable of being lubricated by synovial fluid. The use of novel materials and surgical procedures revolutionized the practice of and raised the success rate of this procedure to an ex- ceptionally high level (>90%). Charnley’s total is considered the gold standard for joint replacement; few changes have been made to this pros- thesis design in the past forty years. However, the Charnley does have several disadvantages. One is an unacceptable rate of wear (about 200 μm/year). Metallic and, more commonly, polymeric wear particles cause a severe foreign- body reaction in the tissues that surround the prosthesis, which can lead to implant loosening. The modern field of biomedical owes a great deal to these pi- oneering individuals, who utilized existing knowledge at the interface of materials science and in order to improve the quality of life for others. In a similar manner, current-day biomedical materials researchers who work on porous coatings, bulk metallic glasses, artificial tissues, and nanostructured biomedical materials are utilizing modern concepts at the interface of materials science and biology in order to further knowledge in this rapidly developing area. A Historical Perspective on the Development of Biomedical Materials vii

The goal of this book is to address several core topics in biomedical materials, including the fundamental properties of the materials used in and den- tistry; the interaction between materials and living tissues; leading applications of polymers, metals, and ceramics in medicine; and novel developments in biomedical materials. Homework problems and other material for each chapter can be found at the website http://springer.com/978-0-387-84871-6. We hope that this work will spur productive discussions and interactions among the many groups involved in the development and use of biomedical materials, including biomedical materials researchers, biologists, medical device manufacturers, and medical professionals. Finally, we would like to thank Elaine Tham, Lauren Danahy, and the staff at Springer Science+Business for making this book possible.

Chapel Hill, North Carolina Roger Narayan Contents

Part I The Fundamental Properties of the Materials Used in Medicine and Dentistry

1 Ceramics and Glasses ...... 3 Irene G. Turner 1.1 Introduction ...... 3 1.2 WhatIsaCeramic?...... 4 1.3 CeramicProcessing...... 5 1.4 PowderProcessing...... 5 1.5 DeformationandFracture...... 7 1.6 Transformation Toughening ...... 9 1.7 PressurelessSintering...... 10 1.8 IsostaticPressing...... 10 1.9 Liquid Phase Sintering ...... 12 1.10 TapeCasting...... 13 1.11 CostsofPowderProcessing...... 13 1.12 PorousCeramics...... 13 1.12.1 BurPS ...... 13 1.12.2 FoamedSlips ...... 14 1.12.3 ReticulatedFoams...... 14 1.13 MeasurementofPorosityinPorousCeramics...... 15 1.14 Surface Engineering ...... 16 1.14.1 IonImplantation...... 17 1.14.2 ThermalSprayCoatings...... 17 1.15 GlassesandGlass-Ceramics...... 19 1.15.1 Glasses...... 19 1.15.2 Glass-Ceramics ...... 21 1.15.3 ...... 22 1.15.4 Bone...... 23 1.15.5 MedicalCeramics...... 25 1.15.6 Biomedical Use of Bioceramics ...... 26 1.15.7 Alumina...... 26

ix x Contents

1.15.8 Zirconia ...... 28 1.15.9 ...... 29 1.15.10 Porous Bioceramics ...... 30 1.16 Functional Gradient Materials ...... 33 1.17 Bone Morphogenetic ...... 33 1.18 Hydroxyapatite Coatings ...... 34 1.19 Bioactive Glasses ...... 36 1.20 Conclusion ...... 37 References ...... 38

2 Metallic Biomaterials ...... 41 Robert M. Pilliar 2.1 Introduction – Why Metals? ...... 41 2.2 Metallic Interatomic Bonding ...... 42 2.3 Crystal Structures – Atom Packing in Metals ...... 42 2.4 Phase Transformations – Diffusive and Displacive ...... 43 2.5 DiffusioninMetals...... 47 2.6 Interatomic Forces and Elastic Moduli (Structure-Insensitive Properties) ...... 48 2.7 Plastic Deformation and Structure-Sensitive Properties ...... 51 2.8 Corrosion Resistance ...... 54 2.9 MetalsandProcessesforImplantFabrication...... 54 2.10 Austenitic Stainless Steel (ASTM F 138/139, F 1314, F 1586, F 2229) ...... 55 2.11 Co-basedAlloys ...... 58 2.12 CastCoCrMo(ASTMF75)...... 58 2.13 Wrought CoCrMo (Low- and High-Carbon) (ASTM F 799, F 1537) ...... 62 2.14 Surface Modification of CoCrMo Implants – Porous Coatings for BoneIngrowth...... 65 2.15 Other Co-containing Implant Alloys (ASTM F 562, F 90, F 563, F 1058) ...... 66 2.16 Titanium-BasedAlloys...... 67 2.17 CommercialPurityTi...... 68 2.18 (α + β)TiAlloys...... 69 2.19 β-Ti and Near β-TiAlloys...... 71 2.20 Zr-NbAlloy...... 72 2.21 Ni-TiAlloys(Nitinol)...... 73 2.22 Tantalum...... 74 2.23 Platinum,Platinum-Iridium...... 75 2.24 DentalAlloys...... 75 2.25 DentalAmalgams...... 76 2.26 Dental Casting Alloys – (Au-based, Co- and Ni-based, Ti-based)...... 76 2.27 Wrought Dental Alloys ...... 78 Contents xi

2.28 NewDirections ...... 78 References ...... 79

3 Polymeric Biomaterials ...... 83 Teerapol Srichana and Abraham J. Domb 3.1 Introduction ...... 83 3.2 Nomenclature ...... 83 3.3 in Medical Applications...... 84 3.4 InertPolymers...... 87 3.4.1 Silicones ...... 87 3.4.2 Polyacrylates ...... 89 3.4.3 PolyethyleneandRelatedPolymers...... 90 3.4.4 Polyamides...... 93 3.4.5 Polyurethane and Polyurea ...... 94 3.4.6 Polyesters...... 95 3.4.7 Polyethers...... 95 3.5 Natural Biopolymer ...... 96 3.5.1 and Gelatins ...... 96 3.5.2 Fibrin...... 97 3.5.3 Polysaccharide ...... 97 3.5.4 Glycosaminoglycans ...... 98 3.5.5 Alginates...... 99 3.5.6 and Chitosan ...... 100 3.5.7 Dextran...... 101 3.6 Bioactive Polymers ...... 102 3.6.1 PolymericDrugs...... 103 3.6.2 Polymeric Conjugates/Polymeric Conjugates...... 104 3.6.3 PolymericProdrugs...... 105 3.6.4 TargetedPolymericDrug...... 105 3.7 Biodegradable Polymers ...... 106 3.7.1 Polyesters...... 106 3.7.2 Poly(orthoesters)...... 108 3.7.3 ...... 109 3.7.4 Polyanhydrides ...... 109 3.7.5 Poly(phosphate ester) ...... 110 3.7.6 Poly(phosphazenes) ...... 110 3.8 CharacterizationofBiomaterials...... 111 3.8.1 Chemical Properties on the Surfaces ...... 112 3.8.2 Physical Properties of the Surfaces...... 113 3.8.3 AdsorbedandImmobilizedProteinDetermination ...... 114 3.8.4 InVitroCellGrowth ...... 114 3.8.5 Blood Compatibility ...... 114 3.9 Fabrication Technology...... 115 3.9.1 Extrusion...... 115 xii Contents

3.9.2 InjectionMolding...... 117 3.10 Future Trends in Biomedical Uses of ...... 117 References ...... 118

Part II The Interaction Between Materials and Living Tissues

4 Biomaterials: Processing, Characterization, and Applications ...... 123 Damien Lacroix and Josep A. Planell 4.1 Introduction ...... 123 4.2 Bone ...... 123 4.2.1 Bone Composition and Structure ...... 123 4.2.2 Biomechanical Properties of Bone ...... 126 4.2.3 BoneRemodeling...... 129 4.3 Cartilage Biomechanics ...... 130 4.3.1 Cartilage Composition and Structure ...... 130 4.3.2 Biomechanical Properties of Cartilage ...... 133 4.3.3 Cartilage Degeneration ...... 135 4.4 Skin Biomechanics ...... 136 4.4.1 Skin Composition and Structure ...... 136 4.4.2 Biomechanical Properties of Skin...... 137 4.5 Tendon and Ligament Biomechanics ...... 138 4.5.1 Structure and Composition ...... 138 4.5.2 Biomechanical Properties of Tendons and Ligaments . . . . 139 4.6 Muscle Biomechanics ...... 140 4.6.1 Muscle Structure and Composition ...... 140 4.6.2 Biomechanical Properties of Muscles ...... 142 4.7 Blood Vessel and Arterial Biomechanics ...... 143 4.7.1 Composition and Structure of Blood Vessels andArteries...... 143 4.7.2 Biomechanical Properties ...... 145 4.7.3 CriticalClosingPressure...... 146 4.8 Joint Biomechanics ...... 147 4.8.1 Description of Joint Biomechanics ...... 147 4.8.2 Function of Joint Biomechanics ...... 147 4.8.3 Mechanical Stresses of Joints ...... 148 4.9 Conclusion ...... 148 Bibliography...... 149

5 Metal Corrosion ...... 155 Miroslav Marek 5.1 Interaction of Metallic Biomaterials with the Human Body Environment ...... 155 5.2 Electrochemical Reactions on Metallic Biomaterials ...... 156 5.3 Forms of Corrosion of Metallic Biomaterials ...... 170 Contents xiii

5.3.1 UniformDissolution ...... 170 5.3.2 GalvanicCorrosion ...... 171 5.3.3 Concentration Cell Corrosion ...... 173 5.3.4 Pitting and Crevice Corrosion ...... 174 5.3.5 Environment Induced Cracking ...... 176 5.3.6 Intergranular Corrosion ...... 177 5.3.7 Wear-Corrosion, Abrasion-Corrosion, Erosion-Corrosion, Fretting ...... 178 5.4 Corrosion Testing of Metallic Biomaterials ...... 178 References ...... 181

6 Wear ...... 183 Chunming Jin and Wei Wei 6.1 Introduction ...... 183 6.2 Friction,Lubrication,andWear...... 183 6.3 Wear Classifications and Fundamental Wear Mechanisms ...... 185 6.3.1 Adhesive Wear ...... 186 6.3.2 FatigueWear...... 187 6.3.3 AbrasiveWearandThird-BodyWear ...... 188 6.3.4 Chemical(Corrosive)Wear...... 189 6.4 WearinBiomedicalDevicesandBiomaterials...... 190 6.4.1 WearinProsthesesandBiomedicalDevices...... 190 6.4.2 Wear Resistance of Biomedical Materials ...... 191 6.5 Summary ...... 196 References ...... 196

7 Inflammation, Carcinogenicity and Hypersensitivity ...... 201 Patrick Doherty 7.1 Introduction ...... 201 7.2 Granulation Tissue ...... 201 7.3 Foreign Body Response ...... 202 7.4 Repair ...... 203 7.5 AcuteandChronicInflammation...... 204 7.6 Infection...... 206 7.7 Local and Systemic Responses ...... 207 7.8 Soft and Hard Tissue Responses ...... 207 7.9 Blood–Material Interactions ...... 209 7.10 ...... 210 7.11 Carcinogenicity ...... 212 7.12 Hypersensitivity ...... 213 References ...... 214

8 Protein Interactions at Material Surfaces ...... 215 Janice L. McKenzie and Thomas J. Webster 8.1 Introduction ...... 215 xiv Contents

8.2 Protein Properties ...... 215 8.2.1 Structure...... 216 8.2.2 Isoelectric Point and Solubility ...... 223 8.2.3 Hydrophobic Composition ...... 223 8.3 Material Surface Properties ...... 223 8.3.1 Surface Topography ...... 224 8.3.2 SurfaceEnergy...... 226 8.3.3 SurfaceChemistry...... 227 8.4 Protein on Surfaces ...... 228 8.4.1 Kinetics and ...... 229 8.4.2 Density ...... 230 8.4.3 Conformation...... 230 8.4.4 ExtracellularMatrixProteins...... 231 8.4.5 Cell Adhesive Sequences...... 232 8.5 Nanoscale Biomaterials ...... 234 8.6 Conclusions ...... 235 References ...... 236

9 Sterility and Infection ...... 239 Showan N. Nazhat, Anne M. Young, and Jonathan Pratten 9.1 Sterilization...... 239 9.1.1 SteamAutoclaves...... 239 9.1.2 DryHeat...... 241 9.1.3 Radiation...... 241 9.1.4 EthyleneOxide...... 241 9.1.5 New Technologies ...... 242 9.2 BiomaterialsAssociatedInfections...... 242 9.2.1 Biofilms...... 242 9.2.2 Types of Medical Related Biofilms ...... 244 9.2.3 InfectionsAssociatedwithImplantableDevices...... 245 9.3 The Use of Antibiotics in the Treatment of Biomaterials AssociatedInfections...... 248 9.3.1 SystemicAntibioticProphylaxis...... 248 9.3.2 Local Delivery of Antibiotics and Antimicrobial Agents . . 249 9.4 DevelopingInfection-PreventingBiomaterials...... 250 9.5 Case Study: Oral Infections and Biomaterials ...... 252 9.5.1 DentalCariesandPeriapicalDisease...... 252 9.5.2 Periodontal Disease ...... 256 References ...... 258

10 Biocompatibility Testing ...... 261 Kirsten Peters, Ronald E. Unger, and C. James Kirkpatrick 10.1 Introduction ...... 261 10.2 Sample Preparation ...... 262 10.3 MammalianCellCulture ...... 263 Contents xv

10.3.1 CytotoxicityTesting...... 268 10.3.2 Hemocompatibility ...... 275 10.3.3 Hypersensitivity/Allergic Responses ...... 279 10.3.4 Genotoxicity ...... 282 10.3.5 Tissue Specific Aspects of Biocompatibility Testing . . . . . 286 10.4 Animal Experimentation ...... 287 10.5 Alternatives to Animal Experimentation ...... 288 References ...... 290

Part III Applications of Polymers, Metals, and Ceramics in Medicine

11 Biomaterials for Dental Applications ...... 295 Sarit B. Bhaduri and Sutapa Bhaduri 11.1 Introduction ...... 295 11.2 Historical Perspectives ...... 296 11.3 MetalsforDentalApplication...... 296 11.3.1 Amalgams...... 296 11.3.2 Biocompatibility of Dental Amalgams...... 298 11.3.3 CastingAlloys ...... 298 11.3.4 Wrought Alloys as Orthodontic Wire ...... 302 11.3.5 DentalImplants ...... 304 11.4 CeramicsforDentalApplications...... 313 11.4.1 Metal-CeramicRestorations...... 314 11.4.2 All-CeramicRestorations...... 315 11.4.3 ProcessingofAll-CeramicRestorations...... 317 11.4.4 SelectionGuideforAll-CeramicRestorations...... 318 11.4.5 ClinicalFailureofAll-CeramicCrowns ...... 319 11.4.6 Bioactive Glasses ...... 319 11.5 PolymersforDentalApplications...... 320 11.5.1 Dentures ...... 320 11.5.2 DentalCements ...... 320 11.5.3 CompositeDentalMaterials...... 322 11.6 Closure...... 323 References ...... 323

12 Ophthalmic Biomaterials ...... 327 Rachel L. Williams and David Wong 12.1 Introduction ...... 327 12.2 Oxygen Delivery ...... 328 12.3 Refraction...... 330 12.4 TissueProtection...... 332 12.5 TissueIntegration ...... 333 12.5.1 ArtificialCorneaTransplants ...... 334 12.5.2 ArtificialEye...... 335 xvi Contents

12.5.3 RetinalImplants...... 337 12.6 Modulation of Wound Healing ...... 339 12.7 Interfacial Tension and Tamponade ...... 340 12.8 Concluding Remarks ...... 345 References ...... 346

13 Hip Prosthesis ...... 349 Afsaneh Rabiei 13.1 Introduction ...... 349 13.2 History of Total Hip Replacement ...... 351 13.3 Various Components and Design of THR ...... 352 13.3.1 Socket or Acetabular Cup ...... 353 13.3.2 TheBall...... 354 13.3.3 Stem...... 354 13.3.4 FixationofTHR...... 354 13.4 VariousMaterialsforTHR...... 356 13.4.1 Alumina...... 357 13.4.2 Yttria Stabilized Zirconia ...... 358 13.4.3 Polyethylene...... 359 13.4.4 Cobalt Based Alloys...... 360 13.4.5 TitaniumBasedAlloys ...... 362 13.4.6 Coatings ...... 363 13.5 DesignVariationofTHR...... 365 References ...... 366

14 Burn Dressing Biomaterials and ...... 371 Lauren E. Flynn and Kimberly A. Woodhouse 14.1 Introduction ...... 371 14.2 PhysiologyoftheSkin...... 371 14.2.1 Basic Organization and Cellular Composition ...... 372 14.2.2 TheEpidermis...... 374 14.2.3 TheDermis...... 377 14.2.4 TheDermal-EpidermalJunctionZone...... 378 14.2.5 The Hypodermis ...... 379 14.2.6 The Appendages ...... 379 14.2.7 Functions of the Skin ...... 381 14.3 DevelopmentoftheIntegumentarySystem...... 382 14.3.1 TheEpidermis...... 382 14.3.2 TheDermis...... 382 14.3.3 The Appendages ...... 383 14.4 Burns...... 383 14.4.1 BurnClassification...... 383 14.4.2 Principles of Burn Wound Healing ...... 384 14.4.3 Immune System Response to Burn Injury ...... 386 14.4.4 Complications...... 387 Contents xvii

14.5 Conventional Treatment of Burns ...... 387 14.5.1 TreatmentofMinorBurns...... 387 14.5.2 PrimaryTreatmentofSevereBurns...... 388 14.5.3 Autografting: The Current Gold Standard ...... 389 14.5.4 Biological Alternatives for Temporary Wound Coverage ...... 390 14.6 Burn Dressing Biomaterials and Tissue Engineering ...... 392 14.6.1 DesignCriteria...... 392 14.6.2 Skin Substitutes ...... 394 14.6.3 Growth Factor Incorporation ...... 402 14.6.4 EpidermalStemCells ...... 402 14.7 FutureOutlook...... 402 References ...... 404

15 Natural and Synthetic Polymeric Scaffolds ...... 415 Diana M. Yoon and John P. Fisher 15.1 Introduction ...... 415 15.2 Natural Polymers for Scaffold Fabrication ...... 415 15.2.1 Polysaccharides ...... 417 15.3 Polypeptides ...... 419 15.3.1 Collagen ...... 419 15.4 Synthetic Polymers for Scaffold Fabrication ...... 421 15.4.1 Polyesters...... 421 15.4.2 Other Synthetic Polymers ...... 426 15.5 Fabrication Techniques ...... 428 15.5.1 Conventional Techniques ...... 428 15.5.2 Rapid Prototyping or Freeform Fabrication Techniques ...... 430 15.6 Properties for Scaffold Design ...... 431 15.6.1 PolymerAssembly...... 431 15.6.2 Surface Properties ...... 432 15.6.3 Macrostructure...... 432 15.6.4 Biocompatibility ...... 433 15.6.5 Biodegradability ...... 434 15.6.6 Mechanical Properties ...... 435 15.7 Summary ...... 435 References ...... 436

16 BioMEMS ...... 443 Florent Cros 16.1 MEMS General Introduction ...... 443 16.2 BioMEMS General Presentation ...... 444 16.2.1 WhatAreThey?...... 444 16.2.2 WhyBuildingBioMEMS?...... 446 16.2.3 Risks and Drawback Associated to BioMEMS ...... 448 xviii Contents

16.3 BioMEMSDesign,MaterialsandFabrication...... 449 16.3.1 BioMEMSDesign...... 449 16.3.2 BioMEMS: Importance of Materials and Materials Characterization ...... 450 16.3.3 MaterialforBioMEMS...... 452 16.3.4 Biocompatibility of MEMS Materials ...... 456 16.3.5 BioMEMS Fabrication Techniques ...... 456 16.4 BioMEMSApplicationReview...... 465 16.4.1 BioMEMSClassification...... 465 16.4.2 BioMEMSforCellCulturing...... 466 16.4.3 BioMEMS for DNA, Proteins and Chemical Analysis. . . . 467 16.4.4 BioMEMS for In-Vivo Applications: Interfacing with theNervousSystem ...... 469 16.4.5 Micro-SurgicalTools...... 470 16.5 Conclusion ...... 471 References ...... 471

17 Magnetic Particles for Biomedical Applications ...... 477 Raju V. Ramanujan 17.1 Introduction ...... 477 17.2 Magnetism and Magnetic Materials ...... 478 17.2.1 Categories of Magnetic Materials ...... 479 17.2.2 The Influence of ...... 481 17.2.3 Magnetization Processes in Ferromagnetic and Ferrimagnetic Materials ...... 481 17.2.4 Factors Affecting Magnetic Properties ...... 482 17.3 PhysicalPrinciples ...... 483 17.4 Examples and Property Requirements of Magnetic Biomaterials...... 485 17.5 Applications...... 486 17.5.1 Magnetic Separation ...... 486 17.5.2 DrugDelivery...... 487 17.5.3 Radionuclide Delivery ...... 488 17.5.4 GeneDelivery...... 488 17.5.5 Hyperthermia ...... 488 17.5.6 Magnetic Resonance Imaging Contrast Agent ...... 489 17.5.7 ArtificialMuscle...... 490 17.6 Summary ...... 490 References ...... 491

18 Specialized Fabrication Processes: Rapid Prototyping ...... 493 C.K. Chua, K.F. Leong, and K.H. Tan 18.1 Introduction ...... 493 18.2 Biomedical Applications of Rapid Prototyping-Tissue Engineering Scaffolds ...... 494 Contents xix

18.3 Roles and Pre-Requisites for Tissue Engineering Scaffolds ...... 494 18.4 Conventional Manual-Based Scaffold Fabrication Techniques. . . . . 495 18.5 Computer-Controlled Freeform Fabrication Techniques for Tissue Engineering Scaffolds ...... 496 18.5.1 Solid-Based Techniques...... 497 18.5.2 Powder-Based Techniques ...... 502 18.5.3 Liquid-Based Techniques ...... 505 18.6 Development of CAD Strategies and Solutions for Automated Scaffolds Fabrication ...... 508 18.7 Prostheses...... 512 18.7.1 Integrated Approach to Prostheses Production ...... 513 18.8 CaseStudies...... 515 18.8.1 CaseStudy1:ProstheticEar...... 515 18.8.2 Case Study 2: Prosthetic Forehead ...... 516 18.9 Conclusion ...... 518 References ...... 519

19 Manufacturing Issues ...... 525 David Hill 19.1 Patents...... 526 19.1.1 EPC Contracting Countries ...... 530 19.1.2 PCT Contracting Countries ...... 530 19.1.3 Copyright ...... 531 19.1.4 TradeMarks...... 532 19.1.5 RegisteredDesign ...... 532 19.1.6 Finally Litigation ...... 533 19.2 Liability ...... 534 19.3 Quality, Standards, Specifications ...... 538 19.4 Audit...... 538 19.4.1 DesignDossier...... 539 19.5 FMEA...... 540 19.5.1 Standards ...... 541 19.5.2 Specification ...... 543 19.5.3 Manufacturing ...... 543

Index ...... 545 Contributors

Sarit B. Bhaduri Department of Mechanical, Industrial and Manufacturing Engineering and Department of Surgery, University of Toledo, Toledo, OH 43606, USA, [email protected] Sutapa Bhaduri Department of Mechanical, Industrial and Manufacturing Engineering and Department of Surgery, University of Toledo, Toledo, OH 43606, USA, [email protected] C.K. Chua School of Mechanical and Aerospace Engineering, Nanyang Technological University, Singapore 639798, [email protected] Florent Cros Wireless Sensor Division, CardioMEMS, Inc., Atlanta, GA 30308, USA, [email protected] Patrick Doherty Centre for Lifelong Learning, University of Liverpool, Liverpool L69 3GW, UK, [email protected] Abraham J. Domb Division of Identification and Forensic Sciences (DIFS), HQ Israel Police, Department of Medicinal and Natural Products, School of Pharmacy-Faculty of Medicine, The Hebrew University, Jerusalem, Israel, [email protected] John P. Fisher Fischell Department of Bioengineering, University of Maryland, College Park, MD 20742, USA, jpfi[email protected] Lauren Flynn Department of Chemical Engineering, Queen’s University, Kingston, ON, Canada K7L 3N6, lauren.fl[email protected] David Hill Rocket Medical plc, Washington, Tyne & Wear, NE38 9BZ, England, [email protected] Chunming Jin Department of Biomedical Engineering, North Carolina State University, Raleigh, NC 27695, USA, [email protected] C. James Kirkpatrick Institute of Pathology, Johannes Gutenberg University, Langenbeckstrasse 1, D-55101 Mainz, Germany, [email protected]; [email protected]

xxi xxii Contributors

Damien Lacroix Institute of Bioengineering of Catalonia, C. Baldiri Reixas, 13, 08028 Barcelona, Spain, [email protected] K.F. Leong School of Mechanical and Aerospace Engineering, Nanyang Technological University, Singapore 639798, [email protected] Miroslav Marek School of Materials Science and Engineering, Georgia Institute of Technology, Atlanta, GA 30332-0245, USA, [email protected] Janice L. McKenzie Nanovis, Inc., West Lafayette, IN 47906-1075, USA, Thomas [email protected] Showan N. Nazhat Department of Mining and Materials Engineering, McGill University, Montreal, Quebec, Canada H3A 2B2, [email protected] Kirsten Peters Department of Cell Biology/Junior Research Group, Biomedical Research Center (BMFZ), Schillingallee 69, 18057 Rostock, Germany, [email protected] Robert M. Pilliar Faculty of Dentistry, University of Toronto, Toronto, Ontario, Canada M5G 1G6, [email protected] Josep A. Planell Department of Materials Science and , Technological University of Catalonia, 08028 Barcelona, Spain, [email protected] Jonathan Pratten Division of Microbial Diseases, Eastman Dental Institute, University College London, London, UK, [email protected] Afsaneh Rabiei Mechanical and Aerospace Engineering, Biomedical Engineering, North Carolina State University, Raleigh, NC 27695-7910, [email protected] Raju V. Ramanujan School of Materials Science and Engineering, Nanyang Technological University, Singapore 639798, [email protected] Teerapol Srichana Department of Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Hat Yai 90112, Thailand, [email protected] K.H. Tan School of Mechanical and Aerospace Engineering, Nanyang Technological University, Singapore 639798, kwanghui [email protected] Irene G. Turner Department of Engineering and Applied Science, University of Bath, Bath BA2 7AY UK, [email protected] Ronald E. Unger Johannes Gutenberg University, Institute of Pathology, REPAIR Lab, Langenbeckstr 1, D-55101 Mainz, Germany, [email protected] Thomas J. Webster Division of Engineering, Brown University, Providence RI 02912 USA, Thomas [email protected] Wei Wei Department of Materials Science and Engineering, North Carolina State University, Raleigh, NC 27695, USA, [email protected] Contributors xxiii

Rachel L. Williams Clinical Engineering and Ophthalmology, School of Clinical Sciences, University of Liverpool, Liverpool L69 3GA UK, [email protected] David Wong St Paul’s Eye Unit, Royal Liverpool University Hospital, Liverpool L7 8XP, UK; The LKS Faculty of Medicine, Eye Institute, HBHA Centre, University of Hong Kong, Hong Kong, [email protected] Kimberly A. Woodhouse Department of Chemical Engineering and Applied Chemistry, Institute of Biomaterials and Biomedical Engineering, Sunnybrook and Women’s College Health Sciences Centre, University of Toronto, Toronto, ON, Canada, [email protected] Diana M. Yoon Department of Chemical and , University of Maryland, College Park, MD 20742, USA, [email protected] Anne M. Young Biomaterials and Tissue Engineering Division, UCL Eastman Dental Institute, University College London, 256 Grays Inn Road, London, WC1X 8LD, UK, [email protected]